Archive
Cluster headaches

FDA has approved suzetrigine (Journavx) for the treatment of moderate to severe acute pain. The drug was found to be as effective as Vicodin (hydrocodone with acetaminophen) after surgery to remove a bunion and after a “tummy tuck”.

Suzetrigine is a selective NaV1.8 inhibitor, targeting a key sodium channel involved in pain signaling. The NaV1.8 channel is crucial in transmitting nerve pain signals to the brain. However, the drug does not enter the brain and works only on the nerves outside the brain and in the body.

Unlike traditional pain medications such as opioids, suzetrigine provides effective pain relief without addiction risk or severe systemic side effects. Early clinical trials suggest it may be beneficial for conditions like neuropathic pain, post-surgical pain, and chronic pain syndromes. Hopefully, it will also prove effective in the treatment of migraines and other types of headaches.

In clinical trials, about 37% of patients experienced adverse events, though most were mild. These included itching, rash, constipation, and muscle spasms.

As a non-opioid option, suzetrigine provides clinicians with an additional tool for acute pain management. The medication is expected to become available in the second quarter of 2025. The expected cost is about $15 a pill.

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It’s an honor to have contributed, alongside Andrew Blumenfeld and Sait Ashina, a chapter on Botox injections to the upcoming textbook Headache and Facial Pain Medicine. Edited by Sait Ashina of Harvard Medical School and published by McGraw Hill, the book is set for release in 2025 but is already available on Amazon.

The book includes chapters on Primary Headaches, Secondary Headaches, Facial Pain and Cranial Neuralgias, Special Treatments and Procedures, Special Populations, and Special Topics. It is an excellent textbook for health care providers.

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Hemicrania continua, a rare but severe headache condition, literally means “continuous one-sided headache” in Latin. This chronic condition manifests as an intense, unrelenting pain concentrated on one side of the head, typically around the eye area. It is more common in women.

The condition often presents with distinctive features beyond the constant one-sided pain. Patients frequently experience:

  • Redness and tearing of the affected eye

  • Nasal congestion and runny nose

  • Forehead and facial sweating

  • Eyelid swelling

  • Pupil size changes

  • Restlessness or agitation

The diagnosis of hemicrania continua can be particularly challenging, especially when the only symptom is a one-sided headache. Doctors often misdiagnose it as migraine or tension headache because of its rarity and overlap with other headache types.

What makes hemicrania continua unique is its remarkable response to indomethacin, a powerful non-steroidal anti-inflammatory drug (NSAID). The response to this medication is so dramatic that hemicrania continua is one of two headache types that are called indomethacin-sensitive headaches.

While indomethacin is highly effective, some patients may experience stomach-related side effects. For those who cannot tolerate indomethacin, several alternatives exist:

  • Other NSAIDs (though generally less effective)

  • Boswellia, an herbal supplement with anti-inflammatory properties

  • Botox injections

Chronic paroxysmal hemicrania shares features with hemicrania continua but differs in its pattern. It causes more intense pain attacks lasting minutes but occurring many times throughout the day. Like hemicrania continua, it also responds extremely well to indomethacin.

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Repetitive transcranial magnetic stimulation (rTMS) is approved by the FDA for the treatment of depression and anxiety. We have been using it to treat migraine headaches and other neurological conditions that are not responsive to standard therapies. Improvement in headaches and pain may be at least in part due to improvement in depression. However, additional mechanisms play a role since we see patients who are not depressed but whose pain improves with rTMS.

A new study by Chinese and Australian researchers published in Pain suggests that opioid mechanisms (endorphins, encephalin, and other peptides) may underlie the mechanism of pain relief produced by rTMS.

This was a double-blind, placebo-controlled study. 45 healthy participants were randomized into 3 groups: one receiving rTMS over the primary motor cortex (M), dorsolateral prefrontal cortex (DLPFC), or sham stimulation. Experimental pain was induced by applying capsaicin (hot pepper extract) over the skin of the right hand followed by application of heat.

Participants received intravenous naloxone (an opioid receptor antagonist) or saline before the first rTMS session to block or allow opioid effects, respectively. After 90 minutes to allow naloxone metabolism, participants received a second rTMS session.

For the M1 group, naloxone abolished the analgesic effects of the first rTMS session compared to saline. Pain relief returned in the second session after naloxone was washed out of the body. For the DLPFC group, only the second prolonged rTMS session induced significant analgesia in the saline condition compared to naloxone. rTMS over M1 selectively increased plasma ?-endorphin levels, while rTMS over DLPFC increased encephalin levels.

The results suggest that opioid mechanisms mediate rTMS-induced analgesia. The specific opioid peptides and rTMS dosage requirements differ between M1 and DLPFC stimulation.

However, these results are far from definitive. The study was small and the study protocol was complicated (e.g. using a double dose of rTMS to DLPFC), which increases the likelihood of an error. Also, these results apply to conditions of acute pain. In patients with chronic pain and headaches, rTMS likely provides relief by improving network connectivity between different parts of the brain.

 

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We use a neuronavigation system from Soterix (on the left) for precise targeting of transcranial magnetic stimulation (TMS). And we use the most advanced TMS machine from MagVenture (on the right) to treat chronic pain, migraines, fibromyalgia, and other neurological conditions.

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The annual course, “The Shifting Migraine Paradigm 2024” will be held February 15-17, 2024 at the Plaza San Antonio Hotel & Spa. This three-day conference offers an excellent update on the treatment of migraine and other headaches.

It is always an honor to be invited to speak at this event. The topic of my presentation is Supplements and Medical Foods.

 

 

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Cluster headaches arguably cause the worst imaginable pain, hence the moniker, suicide headaches.  Fortunately, there are many treatments for this condition, including two FDA-approved drugs. One is sumatriptan injections taken as needed to stop an attack. The other is a preventive monthly injection of galcanezumab (Emgality). We also use Botox injections, oxygen and a variety of medications. Nevertheless, some people do not respond to these treatments.

A report by Japanese neurologists from Tokyo suggests a new treatment. One theory of the origin of cluster headaches is the reactivation of the varicella-zoster virus that causes chickenpox and shingles.

The study included over 160 patients with episodic cluster headaches who received a shingles vaccine. The response to the vaccine was measured by the amount of antibodies in the blood. Those patients who had more antibodies had a longer delay to the next cluster episode than those with low antibody counts. They also found that those who had a COVID infection and received multiple COVID vaccines, tended to do worse.

It is premature to recommend shingles vaccine to patients with cluster headaches unless they are over 50, the age when everyone is advised to get it.

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Zavegepant (Zavzpret), the first CGRP nasal spray for the treatment of acute migraine attacks, was approved by the FDA in March and is now readily available in all US pharmacies..

Zavegepant belongs to the family of CGRP antagonists, which work by blocking excessive amounts of the neurotransmitter CGRP. Elevated levels of CGRP are known to contribute to the development of migraines. By inhibiting its action, zavegepant can effectively stop an ongoing migraine attack. While there are already two oral CGRP medications for the acute treatment of migraines (Nurtec and Ubrelvy), zavegepant is the first nasal spray option. Nasal sprays offer several advantages, including faster onset of action compared to tablets and the ability to bypass the stomach. These benefits are particularly valuable for individuals experiencing migraines accompanied by nausea and vomiting.

Clinical studies have demonstrated that zavegepant is superior to placebo in promptly eliminating all pain and the most bothersome symptom within two hours of administration. The most commonly reported bothersome symptoms associated with migraines are nausea, sensitivity to light (photophobia), and sensitivity to noise (phonophobia).

Side effects of zavegepant were generally mild and infrequent. Participants in clinical trials noted an unpleasant taste in 18% of cases, compared to 4% in the placebo group. Additional side effects included nausea (4% vs. 1%), nasal discomfort (3% vs. 1%), and vomiting (2% vs. 1%). Taste-related issues have been observed with other nasal sprays used for migraines, particularly among patients who experience nausea. However, this can be easily addressed by sucking on a hard candy while using the nasal spray.

Interestingly, even individuals who did not respond to other CGRP drugs may potentially benefit from zavegepant. While these drugs are similar in their mechanism of action, they are not identical, and patients often exhibit strong preferences for a particular medication within the same category. This preference phenomenon is common in other migraine drug categories such as triptans, NSAIDs, and oral CGRP drugs.

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Opportunities & Challenges in the Management of Headache is one of the two annual courses organized by the Diamond Headache Clinic Research & Educational Foundation. This year, it will be held in San Diego from February 16th through February 19th.

The other annual event, Headache Update 2023 will be held in Orlando, Fl from July 13th through July 16th. Both courses have been always well attended and have been receiving very high marks from the attendees.

It’s been my privilege to participate in these annual courses over the past 25 years. This year I will be speaking on February 17th on Nutritional Approaches and Alternative Therapies in Migraine.

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Cluster headaches are considered to cause the worst pain imaginable. We have a variety of medications – both acute and preventive – that help relieve the pain of cluster headaches. For some, none of these treatments work and we do need additional medications. Ketamine could be one such drug.

Ketamine has been in use for over 50 years. Its main indication is intravenous anesthesia. Recently, the FDA approved ketamine nasal spray for depression. It is also being widely used intravenously and by mouth for depression, chronic pain, and migraine headaches. A group of researchers at the Danish Headache Center in Glostrup, Denmark tested the efficacy of ketamine nasal spray for the acute treatment of cluster headaches.

Anja Petersen and her colleagues selected 20 cluster patients whose attacks did not respond sufficiently well to sumatriptan or oxygen – the two most effective acute therapies for cluster headaches. Patients treated a single cluster attack with 15 mg of intranasal ketamine. They could repeat this dose every 6 minutes, for up to 5 times. Four patients took another medication after 15 minutes. Of the 16 remaining ones, 11 had a drop in pain severity by an average of four points, to four or lower on a one to 10 scale. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No patient had any serious side effects from ketamine during the trial.

Ketamine nasal spray that is approved for depression is a more potent version of ketamine called esketamine (Spravato). It is a patented and branded product and it is very expensive. Ketamine itself, however, is a cheap drug. A compounding pharmacy can prepare a nasal spray for as little as $60 for a month supply. Most insurers do not cover compounded drugs, so you’d have to pay for it.

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With Swiss colleagues Drs. Caterina Podella, Livia Granata, and Reto Agosti at the headache conference held on November 4, 2021, in Zürich.
Dr. Podella presented a very comprehensive approach to the treatment of migraine headaches. Dr. Granata expertly covered the topic of cluster headaches. I spoke about the challenges of treating refractory migraine headaches and Dr. Agosti provided a lively and insightful discussion of all these topics.

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The influence of estrogen on migraines in women is well established – women often experience migraines before or during menstruation and ovulation and their migraines usually subside during pregnancy and menopause.

According to a new study published this month by Dutch researchers, men who suffer from migraines often have a deficiency of male hormones.

Gisela Terwindt and her collaborators evaluated a possible deficiency of androgens or male hormones in 534 men with migraine and 437 men with cluster headaches. These men were compared to 152 healthy controls. Two validated questionnaires were used to measure androgen deficiency scores. The researchers controlled for age, weight (BMI), smoking, and lifetime depression. They also measured four sexual symptoms (beard growth, morning erections, libido, and sexual potency). These four symptoms have been shown to differentiate between hormonal deficiency from anxiety and depression. They did not perform blood tests to measure hormone levels.

Patients reported more severe symptoms of clinical androgen deficiency compared with controls. Both patient groups were more likely to suffer from any of the specific sexual symptoms compared to controls (18% migraine, 21% cluster headache, 7% controls).

The findings in men with cluster headaches are not surprising. Prior reports have documented low testosterone levels in this population. A small study by Dr. Mark Stillman suggested that those cluster patients who have low testosterone levels could benefit from hormone replacement therapy.

There are also reports of low testosterone levels in men with chronic migraines but the connection is less established.

This study may prompt me to pay more attention to sexual dysfunction in men with chronic migraines. I may also start checking testosterone levels in such patients.

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